The skeleton, populated by large numbers of osteoblasts and osteocytes, requires a constant supply of energy-rich molecules to fuel the: synthesis, deposition, and mineralization of bone matrix during bone modeling and remodeling. As a result, studies performed over the last decade have expanded our understanding of the physiologic functions of bone beyond locomotion, mineral ion storage, and protection of vital organs to now include the secretion of hormones that contribute to the regulation of whole-body metabolism. Sclerostin, an osteocyte-secreted factor that inhibits Wnt signaling by interacting with the low-density lipoprotein receptor-related protein 5 (Lrp5) and Lrp6 co-receptors, has generally been viewed as a local inhibitor of bone formation. However, human data raises the possibility that sclerostin also antagonizes Wnt signaling in distant tissues as circulating levels are increased in conditions of metabolic dysfunction. Moreover, preliminary studies described in this proposal demonstrate that sclerostin deficiency (Sost-/- mice) alters body composition and glucose homeostasis, and that sclerostin treatment augments adipocyte differentiation. These data lead us to hypothesize that sclerostin fulfills an endocrine function that allows bone to communicate with other metabolically active tissues, and to contribute to the coordination of whole body metabolism. In this application, we will utilize a combination of genetic and pharmacological approaches to explore the impact of sclerostin on adipose tissue development and function. Our hypothesis predicts that circulating sclerostin enhances fat accumulation by suppressing signaling downstream of the Wnt co- receptor Lrp5 and that this function is facilitated by Lrp4, a putative sclerostin receptor. Our approach will enable the identification of previously unanticipated functions of sclerostin. We firmly believe that the information gained from our studies will improve understanding of how the metabolic activity of the skeleton impacts global metabolic activity. Such information is expected to significantly improve the diagnosis, management, treatment, and prevention of the related metabolic disturbances of diabetes and bone disease in aging Veterans.